Compact spheroid formation by ovarian cancer cells is associated with contractile behavior and an invasive phenotype
Abstract
Ovarian cancer cells are present in malignant ascites both as individual cells and as multicellular spheroid aggregates. Although spheroid formation affords protection of cancer cells against some chemotherapeutic agents, it has not been established whether a relationship exists between invasive behavior and predisposition to spheroid formation. Aspects of spheroid formation, including cell‐matrix adhesion, remodeling and contractility are characteristic myofibroblast‐like behaviors associated with fibrosis that contribute to tumor growth and dissemination. We explored the possibility that cell behaviors that promote spheroid formation also facilitate invasion. Our analysis of 6 human ovarian cancer cell lines indicated that ovarian cancer cells possessing myofibroblast‐like properties formed compact spheroids and invaded 3D matrices. These cells readily contracted collagen I gels, possessed a spindle‐like morphology, and had elevated expression of genes associated with the TGFβ‐mediated fibrotic response and/or β1 integrin function, including fibronectin (FN), connective tissue growth factor (CTGF/CCN2), lysyl oxidase (LOX1), tissue transglutaminase 2 (TGM2) and urinary plasminogen activator receptor (uPAR). Whereas cell aggregation was induced by TGFβ, and by β1‐integrin overexpression and activation, these treatments did not stimulate the contractile activity required for spheroid compaction. The positive relationship found between compact spheroid formation and invasive behavior implies a preferential survival of an invasive subpopulation of ovarian cancer cells, as cells in spheroids are more resistant to several chemotherapeutics. Preventing the formation of ovarian cancer spheroids may represent a novel strategy to improve the efficacy of existing therapeutics. © 2008 Wiley‐Liss, Inc.
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Chemoresistance developed in 3D spheroids is observed in vivo as well.
“Such chemoresistance developed in 3D spheroids is observed in vivo as well. 58”
From Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors (2014) · cites this paper as [58]
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- Authors
- Sodek, K. L., Ringuette, M. J., & Brown, T. J.
- Affiliations
- Mount Sinai Hospital (CA)
- Corresponding author
- Brown, Theodore J.
- Venue
- International Journal of Cancer
- Publisher
- Wiley
- Published
- 2009-02-24
- Volume
- 124
- Issue
- 9
- Pages
- 2060-2070
- ISSN
- 0020-7136 (ISSN-L)
- 1097-0215
- OpenAlex
- W2078354424
- Cited by
- 248
- References
- 62
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 7 · 2023: 17 · 2022: 10 · 2021: 16 · 2020: 28 · 2019: 16 · 2018: 17 · 2017: 26 · 2016: 23 · 2015: 16 · 2014: 18 · 2013: 12 · 2012: 15
- FWCI
- 2.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- International Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ovarian Cancer Research Fund
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Keywords
- ovarian cancer, multicellular spheroids, tumor invasion, cell contractility, TGF-beta signaling, beta1 integrin, extracellular matrix remodeling, fibrosis, malignant ascites, chemoresistance, connective tissue growth factor, lysyl oxidase, tissue transglutaminase, fibronectin
- MeSH terms
- Protein Glutamine gamma Glutamyltransferase 2, Cell Adhesion, Cell Movement, Collagen, Extracellular Matrix, Female, Fibroblasts, Fibronectins, Humans, Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase, Neoplasm Invasiveness, Ovarian Neoplasms, Phenotype, Transglutaminases, Tumor Cells, Cultured, Spheroids, Cellular, Integrin beta1, GTP-Binding Proteins, Cell Proliferation, Transforming Growth Factor beta1, Receptors, Urokinase Plasminogen Activator, Connective Tissue Growth Factor
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